3-(Aminomethyl)-5-methylhexanoic acid, which is also called .beta.-isobutyl-.gamma.-aminobutyric acid or isobutyl-GABA, is a potent anticonvulsant. Isobutyl-GABA is related to the endogenous inhibitory neurotransmitter .gamma.-aminobutyric acid or GABA, which is involved in the regulation of brain neuronal activity.
It is thought that convulsions can be controlled by controlling the metabolism of the neurotransmitter .gamma.-aminobutyric acid. When the concentration of GABA diminishes below a threshold level in the brain, convulsions result (Karlsson A., et al., Biochem, Pharmacol., 1974;23:3053-3061), and when the GABA level rises in the brain during convulsions, the seizures terminate (Hayashi T., Physiol, (London), 1959;145:570-578). The term "seizure" means excessive unsynchronized neuronal activity that disrupts normal function.
Because of the importance of GABA as an inhibitory neurotransmitter, and its effect on convulsive states and other motor dysfunctions, a variety of approaches have been taken to increase the concentration of GABA in the brain. In one approach, compounds that activate L-glutamic acid decarboxylase (GAD) have been used to increase concentrations of GABA, as the concentrations of GAD and GABA vary in parallel and increased GAD concentrations result in increased GABA concentrations (Janssens de Varebeke P., et al., Biochem. Pharmacol., 1983;32:2751-2755; Loscher W., Biochem. Pharmacol., 1982;31:837-842; Phillips N., et al., Biochem. Pharmacol., 1982;31:2257-2261). For example, the compound (.+-.)-3-(aminomethyl)-5-methylhexanoic acid, a GAD activator, has the ability to suppress seizures while avoiding the undesirable side effect of ataxia.
It has been discovered that the anticonvulsant effect of isobutyl-GABA is stereoselective. That is, the S-stereoisomer of isobutyl-GABA shows better anticonvulsant activity than the R-stereoisomer. See, for example, Yuen, et al., in Bioorganic & Medicinal Chemistry Letters, 1994;4(6):823-826. Thus, it would be beneficial to have an efficient process for the synthesis of the S-stereoisomer of isobutyl-GABA.
Presently, (S)-3-(aminomethyl)-5-methylhexanoic acid has been prepared by two synthetic routes. These routes each use reactions that require n-butyllithium, and both routes contain a step that must be carried out at low temperatures (.ltoreq.-35.degree. C.) under carefully controlled conditions. These synthetic routes include the use of (4R,5S)-4-methyl-5-phenyl-2-oxazolidinone as a chiral auxiliary to introduce the stereochemical configuration needed in the final product. See, for example, U.S. Ser. No. 08/064,285, which is hereby incorporated by reference. Although these routes provide the target compound in high enantiomeric purity, they are difficult to conduct on large-scale and use expensive reagents which are difficult to handle.
In addition, (.+-.)-isobutyl GABA can be synthesized in accordance with Andruszkiewicz, et al., Synthesis, 1989;953. The synthesis described therein uses potentially unstable nitro compounds, including nitromethane, and an intermediate containing a nitro functional group, which is reduced to an amine in a potentially exothermic and hazardous reaction. The synthesis also uses lithium bis(trimethylsilylamide) at -78.degree. C. The present method does not use nitro compounds, require low temperatures, or require strongly basic conditions.
The present invention provides an efficient synthesis of isobutyl-GABA and provides for the resolution of racemic isobutyl-GABA to obtain the S-stereoisomer of isobutyl GABA that avoids the above-identified problems.